Project Abstract: Sarcopenia, the age-related loss of muscle mass and strength, is an important age-related disorder of the neuromuscular system associated with impaired mobility, loss of independence, and increased risk of mortality. Although exercise appears to have some beneficial effect, there are no proven therapies available, and understanding of the factors driving the degenerative process is incomplete. The neuromuscular system is comprised of groups of muscle fibers innervated by a single alpha motor neuron, motor axon, and synapses, termed a motor unit. The normal development and function of the motor unit is dependent on trophic interaction between muscle and motor neurons. Denervation of muscle fibers results in up to 80% muscle fiber size loss, and similarly retrograde signaling from muscle is important to motor neuron health. Losses of muscle fiber, synaptic, and motor neuron function have all been identified as important factors in aging-related sarcopenia and weakness. The majority of investigations into the mechanisms of sarcopenia have focused on muscle. However, the primary source of degeneration within the motor unit during aging and the temporal aspects of this loss remain unknown, and the neural influence on loss of muscle function with aging has received less attention. We have developed in vivo electrophysiological techniques that allow longitudinal quantification of motor unit function in mouse models that enable quantification of the functional output from a muscle group, the number of functional motor neurons, and synaptic integrity. Our preliminary results demonstrate prominent functional loss from the motor nerve unit pool innervating the hind limb muscles in aging mice suggesting that loss of motor units is a major contributing factor to aging-related muscle weakness and sarcopenia. We hypothesize that loss of motor nerve unit function is the primary mechanism underlying age-related loss of neuromuscular function, however we predict that directly modulating the target tissue (muscle) can preserve motor unit numbers and function. The studies of this proposal will determine the degenerative changes of the motor unit during aging-related muscle loss and identify the components of the neuromuscular system that are most susceptible during aging (Aim 1). Furthermore we will modulate muscle (fiber size and number) via follistatin overexpression to test whether this will maintain or improve neuromuscular function, specifically of the motor neuron and synapse (Aim 2). We hypothesize that loss of motor nerve unit function is an early functional consequence of aging, and that this is associated with subsequent synaptic failure and muscle fiber atrophy and dysfunction. We predict that loss of retrograde signaling of trophic factors from muscle is an important stimulus for sarcopenia development, and therefore we hypothesize that improving muscle fiber size will improve motor neuron function. Our approach is innovative because the techniques that we will utilize allow longitudinal functional assessment of neuromuscular system, and these measures can provide important insight into the interaction of muscle, neuron, and synaptic factors in the development of sarcopenia.